(S)-3-(Aminomethyl)-5-methylhexanoic acid (pregabalin, compound (I)) was first disclosed in EP-A-641330 and is currently being marketed under the trade name Lyrica® as an agent in anticonvulsant therapy. In EP-A-641330 a route for the synthesis of this compound is described. However, the disclosed process to this compound is lengthy (>10 steps), has a low efficiency, and uses pyrophoric or expensive reagents, such as butyl lithium and (+)-4-methyl-5- phenyl-2-oxazolidinone, respectively, which limits its use on an industrial scale.
Structure of pregabalin (I)
In Hoekstra M. S. et al., Org. Proc. & Res. Dev. 1997, 1, 26-38 several routes to pregabalin are described. Two processes of particular economic interest are disclosed in EP-A-828704 and EP-A-830338, respectively. In the '704 patent application, 3-isobutyl glutaric acid, prepared from isovaleraldehyde and ethyl cyanoacetate, serves as a key intermediate, which is transformed via the corresponding cyclic anhydride to an amide which can be resolved in a classical manner with enantiopure phenylethylamine as the resolving agent (scheme 1). The amide is further subjected to a Hoffmann degradation leading to (S)-pregabalin. Improvements and variations of this process have been disclosed in WO 2006/122255, WO 2006/122258, WO 2006/122259, WO 2006/136087, WO 2007/035789, WO 2007/035790, and WO 2007/139933.

In EP-A-830338 racemic 3-(aminomethyl)-5-methylhexanoic acid is prepared and the racemate is resolved by (S)-mandelic acid as a chiral resolution agent. The racemic starting material is prepared in five steps from isovaleraldehyde and diethylmalonate. The resolution of a racemate at the end makes the synthesis costly and inefficient because the undesired isomer has to be taken along the whole process (Scheme 2). A variation of this process with the resolution prior to the reduction of the cyano group was disclosed in WO 2007/143152. Both processes suffer from disadvantages such as lengthy synthesis and low overall yield.

An asymmetric synthesis of an intermediate en route to pregabalin comprising a homogeneous catalytic hydrogenation with chiral phosphine-based ligands was disclosed in WO 2001/55090 and WO 2005/087370. The starting material is prepared in three steps which include the use of carbon monoxide which is a hazardous reagent and Pd which is an expensive catalyst.

In WO 2006/110783 the conversion of chiral 2-(3-methyl-1-nitromethyl-butyl)-malonic acid dialkyl ester to pregabalin using a reduction-decarboxylation strategy was described. The sequence follows a prior art reaction sequence which has been applied to the synthesis, e.g. of baclofen (Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc., 2005, 127, 119-125).
Purification processes leading to pregabalin which is free of some process-related impurities are described in WO 2006/122255 and WO 2006/121557.
All of above described processes make use of chiral auxiliaries, catalysts or additives. Such compound are usually hard to remove and are present in not desirable quantities in the final product.
Enzymatic kinetic resolutions of two nitrile-containing pregabalin precursors (compounds (II) and (III)) have been disclosed in WO 2005/100580 and WO 2006/00904. These two routes describe syntheses of pregabalin which have the disadvantage of using potassium cyanide, the handling of which can be problematic at an industrial scale due to safety reasons. In WO 2007/143113 an enzymatic kinetic resolution via hydrolysis or esterification of four substrates ((IV) and (V); R=H and Et, respectively) is described. However, no experimental details such as selectivity and yields are given.
Structures of compounds which have been subjected to an enzymatic resolution
The synthesis of racemic pregabalin is described in Andruszkiewicz, R.; Silverman, R. B., Synthesis 1989, 953-955. The synthesis starts from (E)-5-methyl-hex-2-enoic acid ethyl ester, which is converted into 5-methyl-3-nitromethyl-hexanoic acid ethyl ester by a conjugate addition of nitromethane. This compound is converted into racemic pregabalin by catalytic hydrogenation followed by saponification.

Recently, an enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester, prepared as described in Andruszkiewicz et al., has been described (Felluga, F. et al. Tetrahedron Asymmetry 2008, 19, 945-955, published online on May 6, 2008). The process described therein uses a particular enzyme, namely Novozyme 435, leading the enantiomerically enriched (S)-5-methyl-3-nitromethyl-hexanoic acid and enantiomerically enriched (R)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester. Good selectivities only can be obtained, if the conversions are below 30% or above 60%, respectively, thus significantly limiting the yields. For the preparation of pregabalin the conversions have to be stopped at <30% in order to obtain (S)-5-methyl-3-nitromethyl-hexanoic acid in the desired quality, which can be further transformed into pregabalin. Higher conversion inevitably led to the formation of byproducts due to occurrence of Nef-type reactions.
Although some processes for the synthesis of pregabalin are available, further improvements in terms of using environmentally benign reagents, of reducing the number of isolated intermediates, and of increasing the overall yield would be highly desirable. Of particular interest are enzymatic methods, which allow the synthesis of (S)-5-methyl-3-nitromethyl-hexanoic acid in yields higher than 30%. Additionally, enzymes which allow the synthesis of (S)-5-methyl-3-nitromethyl-hexanoic acid esters by hydrolyzing the corresponding (R)-5-methyl-3-nitromethyl-hexanoic acid ester are highly desirable.
Additionally, processes which do not make use of chiral auxiliaries or chiral additives, which may be an harmful impurity in the final product, are highly desirable.